Two procedures are commonly used for the conversion of carboxylic acid derivatives to α-chloroketones, an important family of pharmaceutical intermediates. In the first approach, exemplified by Powers and Wilcox, J. Am. Chem. Soc., Vol. 92, page 1782, 1970, the carboxylic acid is converted to an acid chloride, which is then treated with diazomethane and finally with hydrogen chloride. However, diazomethane is a highly toxic and explosive gas, making this approach problematic for large-scale manufacture of α-chloroketones. Kowalski et. al., J. Org. Chem., Vol. 50, 5140, 1985 and Vol. 57, 7194, 1992 describe homologation of esters to α-haloketones utilizing the system CH2Br2/LDA/n-BuLi. Chen and Cheng, Tetrahedron Letters, Vol. 38, No. 18, pages 3157-3178, 1997 subsequently disclosed that higher yields could be achieved by substituting iodochloromethane for dibromomethane in the preceding process. However, this approach is disadvantageous in that cryogenic temperatures are required and, in the latter case, toxic and high-boiling chlorodiiodomethane is a side-product. Thus it is evident that a need exists for a safe and efficient process for the manufacture of α-chloroketones.
A process for preparing α-haloketones is described by König and Mezger in Chem. Ber., Vol. 98, pages 3733-3747, 1965. The disclosed process involves the reaction of dimethylsulfoxonium methylide with isocyanates and ketenes to form β-keto sulfoxonium ylides. On page 3738, in Table 3, there is disclosed treatment of the β-keto sulfoxonium methylides with hydrochloric acid or bromine to form α-chloroketone or α,α-dibromoketone. Subsequently, Degraw and Cory, Tetrahedron Letters, No. 20, pages 2501-2502, 1968, disclosed the preparation of α-acetoxy and α-halomethylketones by the action of acids on acyloxosulfonium ylides generated by other means.
Corey and Chaykovsky, J. Am. Chem. Soc., Vol. 86, pages 1640-1641, 1964 found that the ethyl ester of an α,β-unsaturated acid but which did not contain a fluorine substituent did not react with dimethylsulfoxonium methylide at the ester functionality. Instead the sulfur ylide underwent Michael addition to the C═C double bond. In contrast, these authors teach that phenyl esters of typical (non-fluorine-containing) carboxylic acids do react with dimethylsulfoxonium methylide to form β-keto sulfoxonium ylides. In similar fashion Nagao et. al., J. Am. Chem. Soc., Vol. 104, No. 7, pages 2079-2081, 1982 examined the reaction of the methyl ester of a non-fluorine-containing carboxylic acid with dimethylsulfoxonium methylide. Again no reaction of the ester functionality is observed and the reagent instead effects cleavage of a carbon-nitrogen bond elsewhere in the molecule. The different behavior of the fluorine-containing esters is consistent with the fact that fluorine is by far the most electronegative element on the periodic table. Based on these precedents, one skilled in the art might reasonably conclude that fluorine substitution is required to promote the homologation of alkyl esters to β-keto sulfoxonium ylides by treatment with dimethylsulfoxonium methylide.
Consistent with this supposition, Kronenthal and Schwinden, U.S. Pat. No. 6,399,793, discloses a process for the preparation of α′-N-acyl-α′-chloroketones using phenyl esters as starting material. This reference does not, however, teach or suggest preparation of the sulfoxonium ylides using readily available alkyl esters such as methyl or ethyl esters, though such starting materials would present desirable advantages. These advantages include the fact that alkyl esters can be prepared directly from the corresponding acids without the intermediacy of a hydrolytically sensitive acid chloride as well as the formation of volatile alcohols as side products upon treatment with dimethylsulfoxonium methylide, which simplifies product isolation. Such a desirable preparation has now been achieved in the present invention.